Rheumatoid arthritis (RA) is one of the most common chronic inflammatory conditions in developed countries and is a common cause of disability. RA is an autoimmune disease that causes chronic inflammation of the joints. RA can also cause inflammation of the tissue around the joints, as well as in other organs in the body. Autoimmune diseases are illnesses that occur when the body's tissues are mistakenly attacked by their own immune system. The immune system is a complex organization of cells and antibodies designed normally to “seek and destroy” invaders of the body, particularly infections. Patients with autoimmune diseases have antibodies in their blood that target their own body tissues, where they can be associated with inflammation. Because it can affect multiple other organs of the body, RA is considered a systemic illness. The exact etiology of RA is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, Textbook of Pain, 397-407 (1994)).
It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, Ann Pharmacother., 2002, 36, 679-686; McCarthy et al., Textbook of Pain, 387-395 (1994)). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.
People with RA have a broad range of options for treatment, and doctors may try several RA medication combinations before they find the one that works best for a patient. RA medications include: corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics and disease modifying antirheumatic drugs (DMARDs).
Corticosteroids may reduce some joint damage by reducing inflammation, but their limited effectiveness and high rate of side effects do not make corticosteroids a good long-term treatment strategy. Corticosteroid medications can be given orally or injected directly into tissues and joints. They are more potent than NSAIDs in reducing inflammation and in restoring joint mobility and function. Corticosteroids are useful for short periods during severe flares of disease activity or when the disease is not responding to NSAIDs. However, corticosteroids can have serious side effects, especially when given in high doses for long periods of time. These side effects include weight gain, facial puffiness, thinning of the skin and bone, easy bruising, cataracts, risk of infection, muscle wasting, and destruction of large joints, such as the hips. Corticosteroids also carry some increased risk of contracting infections.
Prednisone is an oral, synthetic corticosteroid used for suppressing the immune system and inflammation. It has effects similar to other corticosteroids such as triamcinolone, methylprednisolone, prednisolone and dexamethasone. These synthetic corticosteroids mimic the action of cortisol (hydrocortisone), the naturally-occurring corticosteroid produced in the body by the adrenal glands. Corticosteroids have many effects on the body, but they most often are used for their potent anti-inflammatory effects, particularly in those conditions in which the immune system plays an important role. Such conditions include arthritis, colitis, asthma, bronchitis, certain skin rashes, and allergic or inflammatory conditions of the nose and eyes. Prednisone is inactive in the body and, in order to be effective, first must be converted to prednisolone by enzymes in the liver. Therefore, prednisone may not work as effectively in people with liver disease whose ability to convert prednisone to prednisolone is impaired. Side effects of prednisone and other corticosteroids range from mild annoyances to serious, irreversible damage, and they occur more frequently with higher doses and more prolonged treatment. Side effects include retention of sodium (salt) and fluid, weight gain, high blood pressure, loss of potassium, headache and muscle weakness. Prednisone also causes puffiness of the face (moon face), growth of facial hair, thinning and easy bruising of the skin, impaired wound healing, glaucoma, cataracts, ulcers in the stomach and duodenum, worsening of diabetes, irregular menses, rounding of the upper back (“buffalo hump”), obesity, retardation of growth in children, convulsions, and psychiatric disturbances. The psychiatric disturbances include depression, euphoria, insomnia, mood swings, personality changes, and even psychotic behavior.
NSAIDs relieve symptoms and mild inflammation but do not have any modifying effect on the disease itself. Acetylsalicylate, naproxen, ibuprofen, and etodolac are examples of NSAIDs. NSAIDs are medications that can reduce tissue inflammation, pain, and swelling. The newer NSAIDs are effective in reducing inflammation and pain requiring fewer dosages per day. Patients' responses to different NSAID medications vary. The most common side effects of aspirin and other NSAIDs include stomach upset, abdominal pain, ulcers, and even gastrointestinal bleeding. Additional medications are frequently recommended to protect the stomach from the ulcer effects of NSAIDs. These medications include antacids, sucralfate, proton-pump inhibitors, and misoprostol. Newer NSAIDs include selective Cox-2 inhibitors, such as celecoxib, which offer antiinflammatory effects with less risk of stomach irritation and bleeding risk. Analgesics include creams (capsaicin) or pain medication pills such as propoxyphene or oxycodone.
DMARDs can slow, and sometimes even prevent, joint damage, and destruction associated with rheumatoid arthritis. They include leflunomide, sulfasalazine, hydroxychloroquine, and methotrexate. Methotrexate is the most commonly prescribed first-line treatment for RA because it provides quick relief and has a relatively low rate of side effects. Biologic DMARDs are a newer group of drugs derived from living organisms. These medications block various elements of the immune system that can fuel inflammation. They include medications etanercept, infliximab, anakinra, adalimumab, rituximab and abatacept.
Etanercept, infliximab, and adalimumab are biologic medications that intercept a messenger protein in the joints called tumor necrosis factor (TNF) that promotes inflammation of the joints in RA. These TNF-blockers intercept TNF before it can act on its natural receptor to “switch on” inflammation. This effectively blocks the TNF inflammation messenger from recruiting the cells of inflammation. Symptoms can be significantly, and often rapidly, improved in patients using these drugs. Etanercept must be injected subcutaneously once or twice a week. Infliximab is given by infusion directly into a vein (intravenously). Adalimumab is injected subcutaneously either every other week or weekly. Each of these medications is being evaluated by doctors in practice to determine what role they may have in treating patients in various stages of rheumatoid arthritis. Research has shown that biological response modifiers also prevent the progressive joint destruction of rheumatoid arthritis. They are currently recommended for use after other second-line medications have not been effective. The biological response modifiers (TNF-inhibitors) are expensive treatments. They are also frequently used in combination with methotrexate and other DMARDs, because the TNF-blocking biologics are more effective when combined with methotrexate.
Anakinra is another biologic treatment that is used to treat moderate to severe rheumatoid arthritis. Anakinra works by binding to a cell messenger protein (IL-1, a proinflammation cytokine). Anakinra is injected under the skin daily. Anakinra can be used alone or with other DMARDs. The response rate of anakinra does not seem to be as high as with other biologic medications. Rituximab is an antibody that was first used to treat lymphoma, a cancer of the lymph nodes. Rituximab can be effective in treating autoimmune diseases like RA because it depletes B-cells, which are important cells of inflammation and in producing abnormal antibodies that are common in these conditions. Rituximab is now available to treat moderate to severely active RA in patients who have failed treatment with the TNF-blocking biologics. Preliminary studies have shown that rituximab was also found to be beneficial in treating severe RA complicated by blood vessel inflammation (vasculitis) and cryoglobulinemia. Abatacept is a biologic medication that blocks T-cell activation to treat adult patients who have failed treatment with a traditional DMARD or TNF-blocking biologic medication.
Glycyrrhetinic acid, a non-selective inhibitor of both 11β-hydroxysteroid dehydrogenase type 1 and 2 isozymes (11β-HSD-1 and 11β-HSD-2), has been identified as a possible drug for RA (International Publication WO2005/027882). However, inhibition of 11β-HSD-2 causes serious side effects, such as hypertension.
11β-HSD-1 is a low affinity enzyme with Km for cortisone in the micromolar range that prefers NADPH/NADP+ (nicotinamide adenine dinucleotide phosphate) as cofactors. 11β-HSD-1 is widely expressed and particularly high expression levels are found in liver, brain, lung, adipose tissue, bone and vascular smooth muscle cells. Many studies have shown that 11β-HSD-1 functions primarily as a reductase in vivo and in intact cells. It converts inactive 11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) to active 11-hydroxyglucocorticoids (i.e., cortisol or corticosterone), and thereby amplifies glucocorticoid action in a tissue-specific manner.
The present application describes the utility of the selective inhibitors of 11β-HSD-1 in the treatment of inflammation, chronic inflammation, pain, RA, osteoarthritis and osteoporosis.